Signal transduction is a fundamental mechanism whereby extracellular stimuli are relayed to the interior of cells. These signals regulate a wide variety of physical responses in the cell including proliferation, differentiation and apoptosis. Many of these signal transduction processes utilize the reversible phosphorylation process of proteins involving specific protein kinases and phosphatases.
There are two classes of protein kinases (PKs): the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs). PTKs can phosphorylate tyrosine residue on a protein. STKs can phosphorylate serine or/and threonine residue. Tyrosine kinases can be divided into either the receptor-type (receptor tyrosine kinase, RTKs) or the non-receptor type (non-receptor tyrosine kinase). Now about 90 tyrosine kinases have been identified in the human genome, of which about 60 belong to the receptor type and about 30 belong to the non-receptor type.
The Receptor Tyrosine Kinases (RTKs) family includes: (1) the EGF family of receptor tyrosine kinases such as the EGFR, HER-2, HER-3 and HER-4; (2) the insulin family of receptor tyrosine kinases such as the insulin receptor (IR) and insulin-like growth factor-I receptor (IGF-IR) and insulin-related receptor (IRR); (3) the Class III family of receptor tyrosine kinases such as the platelet-derived growth factor (PDGF) receptor tyrosine kinases, the stem cell factor receptor tyrosine kinase SCF RTK (commonly known as c-Kit), the fins-related tyrosine kinase 3 (Flt3) receptor tyrosine kinase and the colony-stimulating factor 1 receptor (CSF-1R) tyrosine kinase and the like. Otherwise, hepatocyte growth factor receptor(HGFR)c-Met and vascular endothelial growth factor (VEGFR) belong to RTKs family. They play critical role in the control of cell growth and differentiation and are key mediators of cellular signals leading to the production of cytokines such as growth factors (Schlessinger and Ullrich, Neuron 1992, 9, 383).
EGFR(ErbB, HER) play critical role in the control of cell proliferation and growth. These RTKs consist of an extracellular glycosylated ligand binding domain, a transmembrane domain and an intracellular cytoplasm catalytic domain. The enzymatic activity of receptor tyrosine kinases can be stimulated by ligand-mediated homodimerization or heterodimerization. Dimerization results in phosphorylation of tyrosine residues on the receptors in catalytic domain, produces a future binding site. This is followed by the activation of intracellular signaling pathways such as those involving the microtubule associated protein kinase (MAP kinase) and the phosphatidylinositol3-kinase (PI3 kinase). Activation of these pathways has been shown to lead to cell proliferation and the inhibition of apoptosis. It has been identified that such mutated and overexpressed forms of tyrosine kinases, like EGFR, HER-2, are present in a large proportion of common human cancers such as breast cancer, prostate cancer, non-small cell lung cancer, oesophageal cancer, ovarian cancer and pancreatic cancer and the like. Prevalence and relevance of tyrosine kinases is confirmed in the oncogenesis and cancer growth.
As the Class III family of receptor tyrosine kinases, the platelet derived growth factor receptor (PDGFR) group, which includes c-Kit and Fins-like tyrosine kinase 3 (FLT-3), has structure and activation process as same as those of EGFR family. They transmit signals through dimerization, subsequently regulate physical responses in the cell proliferation, differentiation, motility, and vascular growth. Therefore members of this family are closely related with the cancer initiation and development. The expression pattern of c-Kit has been studied e.g. in a panel of different primary solid tumors. A high expression of c-Kit could be found inter cilia in small cell bronchial carcinoma, testicular intraepithelial neoplasias, melanomas, mamma carcinomas, neuroblastomas, especially in gastrointestinal stromal tumors (GIST) [see Weber et al., J. Clin. Oncol. 22(14S), 9642 (2004)]. Most (50 to 80%) of GISTS occour through c-Kit gene mutations. Mutations can make c-Kit has continuing activation of receptor tyrosine kinases, leading to a high cell division rate and possibly genomic instability. Thus cancer is induced.
Another important member of receptor tyrosine kinases is the vascular endothelial growth factor receptor (VEGFR). VEGFR is closely involved with angiogenesis. VEGF can activate related signaling pathways to promote angiogenesis by binding with VEGFR. Recent evidence indicates that VEGF can induce endothelial cell proliferation and migration which subsequently leads to the formation of capillary tubes that promote the formation of the hyperpermeable, immature vascular network which nourishs cancer growth. In addition to its angiogenic activity, VEGFR and VEGF may promote tumor growth directly by pro-survival effects in tumor cells. It was observed that VEGFR is highly expressed in a variety of solid malignant tumors, such as lung carcinomas, breast carcinomas, ovarian carcinoma, pancreatic cancer and melanoma. Therefore, the development of tumors can be inhibited by inhibiting VEGFR activation. That is beneficial in the treatment of cancer.
As one member of the RTKs, the hepatocyte growth factor (HGF) receptor (c-Met or HGFR) has been shown in many human cancers to be involved in oncogenesis, tumor invasion and metastasis, as well as enhanced cell motility (see, Ma, P. C. et al. (2003b). Cancer Metastasis Rev, 22, 309-25; Maulik, G. et al. (2002b). Cytokine Growth Factor Rev, 13, 41-59).
As another member of PTKs, Non-receptor Tyrosine Kinases (abbreviated as “NRTKs” or “CTKs”) is the protein tyrosine kinases in cytoplasm. Comparing to RTKs, CTKs are lack of an extracellular function domain and a transmembrane domain. The Tyrosine Kinases activation of CTKs is also closely involved with cancer. A more detailed description of CTKs is provided in Bolen, 1993, Oncogen 8: 2025-2031.
Two main characteristics of cancer are genomic instability and uncontrolled signal pathways for regulating cell cycle and proliferation. Genomic instability leads to changing or losing biological function of key regulting proteins, then interferencing or damaging the signal transduction pathways, and the aberrant signal pathways couldn't regulate and control cell cycle progress and apoptosis normally, while cancer cell can continue to live and proliferate in the state of genetic damage. As the foundation to achieve these regulating progress, PKs including the above discussed RTKs and cytoplasm PTKs (CTKs) are closely involved with oncogenesis and cancer growth, and became the important target for treating cancer.
There is expected to synthetize novel compounds having anti-tumor cell proliferative activities. These compounds are expected to inhibit one or more RTKs, CTKs or STKs, and are useful for treating or ameliorating RTKs, CTKs or STKs mediated, angiogenesis mediated physiological disorders with cell over-proliferation.
Up to now, a series of literatures about protein kinase inhibitors have been disclosed, such as WO00/18761 A1, WO2003089439A1, WO2005028443A1, WO2007055514A1. They disclosed quinoline or quinazoline derivatives, the use and the preparation thereof. Hwei-Ru Tsou et al. in J. Med. Chem. 48, 1107-1131 (2005), also disclosed quinoline derivatives as protein kinase inhibitors.
Although some protein kinase inhibitors for treating cancers have been disclosed, it still need to develop new compounds which have better curative effect and pharmacokinetic absorption. After continuous efforts, the inventor provides new compounds of formula (I) in the present invention, and discovers that these compounds have shown better efficiency and function.